The goal of this proposal is the development of a novel mass spectral method which will permit the sequencing of 500 base-long (or longer) strands of DNA. The realization of this instrument will allow DNA sequencing to be performed at a rate approaching one million bases per day- a rate three orders faster than currently available techniques. To achieve this objective, we plan on melding current DNA sequencing strategies with three new technologies to produce a low-cost, easily automated sequencing method. We intend (i) to draw on our expertise in laser vaporization to develop a new vaporization strategy that will permit precise control over the chemical nature of the desorbed DNA and will be very amenable to rapid sequencing; (ii) to utilize an ionization scheme that will allow selective ionization of the vaporized DNA strands and ultrasensitive detection of these strands; and (iii) to analyze these ionized DNA strands by a mass spectral technique that will have the sensitivity and resolution required to sequence DNA up to 1000 bases long. The automation of the technology we propose would result in an extremely sensitive DNA sequencing method requiring little manual labor. The sequencing cost resulting from an instrument that used this methodology should be less than $0.10 per sequenced base, thus resulting in at least a 10-fold reduction in the sequencing costs associated with the Human Genome Initiative.